Effect of ethacrynic acid on the sodium- and potassium-activated adenosine triphosphatase activity and expression in Old Order Amish bipolar individuals

Abstract Background There are numerous reports of abnormalities in the expression of the sodium- and potassium-activated adenosine triphosphatase (Na,K-ATPase) in response to an ionic stress with ethacrynic acid (ECA) challenge in bipolar subjects. However, all of these studies have been in out-bred populations. In an attempt to reduce the genetic variability associated with this observation, we examined this phenomenon within an isolated breeding population. Methods We studied 36 lymphoblastoid cell lines obtained from Old Order Amish individuals who had bipolar disorder, type I (16), or were unaffected siblings of the same gender (9) or unrelated normal controls(11). Cells were treated with10−5 M ECA for 3 days after which Na,K-ATPase alpha1 protein expression and activity ([3 H]-ouabain binding,86 Rb-uptake, and intracellular sodium and potassium concentrations) were measured. Results Cells from bipolar patients expressed less Na,K-ATPase as measured by immunoblot analysis after ECA treatment (0.94 ± SD 0.13 relative units) compared to unaffected siblings (1.06 ± 0.12, P = 0.029) and Old Order Amish normal controls (1.06 ± 0.14, P = 0.0004). None of the other variables studied were different. Limitations This is a study of peripheral cells which do not express all of the Na,K-ATPase expressed in the brain. The observed difference is small. Conclusions Ethacrynic-acid-stimulated lymphoblast sodium pump expression in Old Order Amish bipolar subjects is reduced compared to Amish controls.